Estrogen-Related Receptor Gamma Deletion in Podocytes Accelerates Aging-Related Kidney Diseases

Background: A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging, per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Previous study in our lab demonstrated the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation by using pan-ERR agonist. However, the contribution of individual isoforms of ERRs has not been addressed. Methods: Since the aging kidney showed a possible compensatory increased expression of ERRγ in the podocytes, we aimed to determine the role of ERRγ in aging podocyte in this study. We cross breed ERRγ floxed mice with podocin-cre mice to achieve a podocyte-specific ERRγ deletion. Results: While these mice at 3-month-old showed no effect on albuminuria compared to the wild type, when the mice were aged to 21 months old, there was a significant increase in albuminuria. Furthermore, we found that instead of inflammation and fibrosis, the podocyte deletion of ERRγ primarily targeted the expression of mitochondrial biogenesis regulator PGC-1α, and mitochondrial fatty acid oxidation enzymes CPT1a and MCAD in the kidney. Conclusion: Considering a significantly decreased expression of ERRα in aging podocytes plus its traditional role in mitochondrial function, these studies using podocyte ERRγ deletion suggested an overlapping mechanism for ERRα/ERRγ to act as modulators of age-related mitochondrial dysfunction to prevent progression of age-related kidney disease. Funding: NIDDK Support